Intellect and emotion after Stroke

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1 Intellect and emotion after Stroke
Hunter Stroke Services Newcastle, NSW 28 October 2008 Thomas Lindén Intellect and emotion after Stroke

2 Thomas Linden CRF @ NSRI 2008 Swedish MD Neurology and Psychiatry
PhD neurology MSc epidemiology Neurorehabilitation @ Sahlgrenska Univ Hosp, Gothenburg, Sweden

3 A global disease Anually, 15 million people suffer a stroke. Of these, 5 million die and another 5 million are left disabled for life, placing a burden on the family and society. Stroke is uncommon in people under 40 years of age. When it occurs, the main reason is often high blood pressure. The incidence of stroke is declining in the western industrialised world, but as populations are ageing, the absolute number of stroke sufferers per year is still increasing. The impact of stroke on developing countries is also increasing.

4 Post-stroke cognitive impairment and dementia
Not new Not rare Not unimportant Not untreatable Not fully known Not new – Thomas Willis described in 1672 ”dullness of mind…forgetfulness…and foolishness” as a sequele of apoplexy. Not rare - it is more likely to experience cognitive impairment than not to do it, also dementia is common Not unimportant – A common history is a previously independent, intelligent, productive, often a soon to be or recently retired person, who suffers an unexpected stroke with minor or moderate persisting motor or language impairments, but suddenly loses his mind or intellectual abilities and becomes dependent of others for his or her basic everyday life, maybe even severe enough to make ones close ones secure dayly care by a regular carer or by moving to an institution. Cognitive impairments is one of the commonest reasons for not being able to live independently. Not untreatable – the likelihood of cognitive deterioration decreases with successful recurrent stroke prevention, with blood pressure and lipid management. Maybe also with anticoagulant and – as we try to find ut within AVERT – with early mobilisation. While manifest, symptomatic treatment is to an extent available. Not fully appreciated – not routinely even screened for in stroke services, even though the easiest screens only take 5 min and can be done bedside Not fully known – Much remains to be done, both in terms of finding new knowledge and of implementation of what is already known. Diagnostic systems are messy and have low validity and biological and clinical markers to increase diagnostic presicion have to be developed.

5 Cognitive impairments in stroke patients – a new finding?
”dullness of mind…forgetfulness…and foolishness” as a sequele of apoplexy Thomas Willis described in 1672 Worse rehabilitation in cognitively impaired Adams GF, Lancet 1963 Advice and support to cognitively imaired and carers often neglected Ebrahim S, Int Disabil Stud 1987. Cognitive impairment after stroke analysed in many studies More complex pathogenesis Relation to other cognitive disorders It is no recent finding that cognitive impairment is common after stroke. Thomas Willis described it already in the 1600s. It has also long been known that stroke patients with cognitive impairments have a worse outcome in rehabilitation. They have higher mortality, longer hospital stay, but less intense training, are less likely to be discharged their home. Further that they are less likely to be selected to an intense rehabilitation programme and that their carers receive less than appropriate support. The epidemiological picture of cognitive impairment after stroke has not been at all clear until quite recently. Difficulties in describing the pathology; both in terms of ethiology, phenomenology and diagnostic labelling and understanding of the basic mechanisms of how and why cognitive impairments evolve. The association to the neurodegenerative cognition impairing diseases keep being a matter of exploration and debate.

6 Cognitive impairment In a systematic review by Leys and coworkers, a pattern across studies were found. Prevalence of dementia seem to increase over time, although mortality is higher in demented individuals and that group therefore is subject to attrition. It must therefore be a recruitment of new cases into the demented group that is higher than the incidence in the population. Also, prevalences were consistantly higher in hospital based studies than in community-based, indicating that selection bias is a concern even in well executed studies. To the right – differences ion CLT in normal ageing, AD and VD. More spatio-constructional and memory problems in AD and more attention-executive problems in VD. But huge overlap. 1 stroke patient in 3 to 6 can be diagnosed with dementa after 3 months. In our Gothenburg 70+ study, investigating elderly stroke patients after 1½ years, one in 4 of the patients had dementia. An additional 50% were shown to have cognitive impairments without fulfilling diagnostic criteria for dementia. 1/3 of the patients had impaired memory, half of them had apraxia.

7 A blurred picture Serious cognitive impariments can exist without dementia criteria being fulfilled (Kotila 1986, Ritchie 1988). To focus on dementia as diagnostic criterium will therefore lead to underestimation of the frequency of cognitive impairment (Bowler&Hachinski 1995). Reports were for long focused on the dementia syndrom, which implies a steady progressive course and mandatory memory impairment. In stroke, other impairments than that of memory, i.e. executive function, are often more prominent, and the course may be fluctuating. If only dementia is used to describe cognitive impairment, a large proportion of the problem will be missed out. Later, cognitive impairment without dementia has been added to the picture more regularly. Vascular cognitive impairment is today more often described as a continuum, from debut of symptoms, through VCI to vascular dementia. Vascular dementia and Alzheimer’s disease both being not all to rare diseases, gives a large space for mixed variants of the diseases as well. Moorhouse&Rockwood, 2008

8 Semantic quagmire Arteriosclerotic dementia Mass effect Multi-infarct dementia Vascular dementia (VaD) Vascular cognitive impairment (VCI) Vascular cognitive disorder (VCD) Cognitive-impairment-no-dementia (CIND) Post-stroke dementia (PSD) Sub-cortical vascular dementia (SCVD) ”Mixed” vascular dementia Jellinger 2008 ? Until the 1960s, dementia in elderly subjects was usually labeled “arteriosclerotic dementia” , originally conceived as an arteriosclerotic disorder arising from low cerebral perfusion as the result of cerebral Infarction. Tomlinson et al. described the relationship between the volume of infarcted tissue and cognitive impairment, suggesting that destruction of large volumes of cortex is necessarily followed by dementia, whereas subtle cerebrovascular lesions (CVL) may or may not contribute to dementia, probably depending on their location. Hachinski et al. criticized this term as both misleading and inaccurate, and coined the term “multi-infarct dementia” (MID) due to the accumulation of cerebral infarct volumes in excess of a critical threshold. Because this phenotype constitutes only a small subdivision of dementias of suggested ischemic–vascular etiology, the term “vascular dementia” (VaD) and others were chosen. Later, they were replaced by “vascular cognitive impairment” (VCI) to acknowledge that the cognitive effects of CVD may be significant, but fall short of a true dementia syndrome as defined by impairment of activities of daily living (ADL). Others proposed the term “vascular cognitive disorder” (VCD) as a global diagnostic category, ranging from VCI to VaD. VCD has been recently limited to cases without dementia, i.e., cognitive impairment-no dementia (VCI-ND), but there are no universally accepted criteria for VCI. Other subgroups include post-stroke dementia (PSD), subcortical vascular dementia and mixed AD plus CVD.

9 Cognitive impairment common after stroke
Dementia in population studies Pooled 11 European studies – 6.4% (Lobo, Neurology, 2000) CSHA: IR %/Y in (Herbert, Stroke 2000) Black>White; Triple in 10Y (Taylor, NeurobiolAg, 2004) 5 years (Henon, Neurology, 2001) VaD of all dementias CSHA – 12% + 13% mixed Rockwood et al, Neurology 2000 Double the frequency of AD in Japan Ueda, Stroke 1992 VaD after stroke Prevalence range 14-32% (Bowler, Lancet Neurology 2008) 3 months (Barba, Stroke 2000) 20 months (Linden, Neuroepid, 2004) 5 years (Henon, Neurology, 2001) VCI 50% in addition to VaD Prevalence of dementias in the population depend on the study population (memory clinic bias), diagnostic systems used and the support of imaging and post-mortem follow-up. Authopsy studies were considered the goldern standard for diagnosis, but are getting critisized for several reasons. Valid biomarkers is a hope for better case ascertainment in the future. Until then, occurence repors should be read with caution. The frequency is thus uncertain and various figures of occurrence have been reported. A collaboration between population-based epidemiological studies within europe (Lobo et al, Neurology, 2000), stated that in 11 pooled studies in subjects over 65, they found an age-standardised prevalence of 6.4% for all dementias, with 16% of all dementias being due to Vad. The CSHA reported 12% VaD and 13% mixed. An american study reported higher frequencies in blacks than whites and reports from NE Asia show a different pattern from Europe and US with 50-60% of all dementia cases being VaD. So, how much of this is attributable to VaD? Again, the estimates should be received with caution. Recently the CSHA published 12% of dementias being VaD with as much more if mixed are added in % seem to be a common figure, but the range is very large. In contrast, several reports from China and Japan attribute VaD to about half of dementias or more. Another way is to look at stroke patients specifically: 1 stroke patient in 3 to 6 can be diagnosed with dementa after 3 months. In our Gothenburg 70+ study, investigating elderly stroke patients after 1½ years, one in 4 of the patients had dementia. An additional 50% were shown to have cognitive impairments without fulfilling diagnostic criteria for dementia. 1/3 of the patients had impaired memory, half of them had apraxia. Another study showed 1/3 of patients demented after 5Y.

10 Authopsy studies of VaD/VCI
Authopsy studies were considered as gold standard used to validate other diagnostic measures in studies. Concerns include referral bias (recruitment from memory clinics) and interrater reliabilities. A meta.analysis of 2,784 cases in the studies in the table until 1990, showed an overall risk of 11%, with a wide range within studies of 2-85% (Markesbery 1998). The Hatchinski group published measures of 15-19% (Mirsen 1998), while the CERAD, Nun study and Florida brain bank produced low occurences (<3%). A recent european study published (Riekse, NA, 2004) a mean 12%, while a recent Japanese study (Seno, geront 1999) produced 35% VaD and another 20% mixed. 1. Classical multiinfarct encephalopathy (MIE) Multiple large (sub/territorial) infarcts in territories of large cerebral arteries. 2. Strategic infarct dementia (SID) Small or medium-sized infarcts/ischemic scars in functionally important brain regions. 3. Small vessel disease (a) Multilacunar state (PIC: OLD LACUNAR INFARCT IN L) CAUDATE NUCL.) (b) Subcortical arteriosclerotic leukoencephalopathy Binswanger (SAE), “leukoaraiosis” (PIC:HYPERTENSIVE MICROANGIOPATHY) Jellinger 2005 Markesbery 11% Mirsen 17% Riekse 12% Seno 35%

11 Clinical diagnosis The tools for separating VaD from other dementias on the grounds of clinical apperance are just not good enough. Several attempts have been made to ease the task for clinitians and researchers. Even the term VaD does not represent a homogenous entity and is therefore hard to define. Hachinski did with his tool formulate an algoritm that would indicate to the clinician on the basis of a clinical scoring whether it was more likely to have a AD och VaD patient at hand. The Ichemic score was developed before the imaging revolution in neuroscience and does not include that in the score. Several attempts to improve the utility in modified versions of the IS have been mande, but none has taken off. The DSM system first defined by means of operational research criteria, algoritms for dementia diagnosis. First in the recent DSM IV, vascular dementia was added in on grounds of signs of vascular disease. It now also accepts executive function as a diagnostic criterium for dementia, while previous versions also had mandatory memory impairment and not executive function in the picture. Spatial difficulties are however recognised by the NINDS-AIREN criteria but not by the DSM. The NINDS-AIREN criteria used a three-step evaluation towards identifying a patient as having VaD on the basis of cognitive impairment, cerebrovascular disease and a relationship between the two. The DSM criteria are sensitive, but less specific than the NINDS-AIREN criteria.

12 Cognitive profiles Alzheimer’s disease/MCI Apraxia Aphasia Depression
Vascualar Dementia/VCI Executive problems Attention Psychomotor speed Emotional lability Alzheimer’s disease/MCI Anterograde memory Spatial abilities Gait and motor OK Apraxia Aphasia Depression Cognitive impairment in vascular and degenerative dementia have different profiles. However there is a great individual variation making diagnosis on the bsis of neuropsychological testing very difficult. A harmonisation committe has published recommendations for standardised testing in the clinic as well as within clinical studies. This is a response to the notion that in many clinical trials physical outcome is extensively followed without the slightest effort on establishing cognitive function. As a very baseline, the consortium propose a five minute assessment for all patients, consisting of a five item immediate and delayed recall test; a six item orientation task and a phonemic fluency task – all from the MoCA. Also they recommend adding TMT and sematic fluency or the entire min test if resources permit.

13 Risk factors for VaD Traditional stroke RF Cerebral hypoperfusion
Hypertension Atrial fibrillation Metabolic syndrome Cerebral hypoperfusion Orthostatism Hippocampal atrophy Nutritients Genetics Obviously vascular disease is a risk factor for VCI and VaD. It has also been shown that the risk for cognitive impairment increases with each recurrent stroke, so ordinary stroke prevention is a baseline for prevention of VCI. The framingham study published a stroke risk profile and later showed that (FSRP, Elias, stroke 2004) increases in the score associated to lower cognitive performance, especially in abstract reasoning, visuo-spatial memory and executive function. The metabolic syndrome has been proposed to predispose for VaD. Hypertension triples the risk (Posner Neurology, 2002) or even more (HAAS). Atrial fibrillation increased the risk for dementia by 2.2 in the Rotterdam study (and in fact associated to Alz also in the absence of stroke). Smoking doubles the risk for VaD, however only for current smokers. Carotid intima thickness increses the risk both for VaD and AD. Cerebral hypoperfusion (Román 2004) as do poor left ventricle function and systolic hypotension (Zuccalá, 2001). Orthostatism is a predictor of white matter disease (Longstreth CVHS, 2001) as is hippocampal atrophy. The roles of homocystein and estrogen are not enough studied to say. Moderate wine consumption seem to lower the risk (1-6 drings/w, CVHS) Genetic factors are also risk factors, exemplified by CADASIL/Notch-3 and familial amyloid angiopathy, butnot ApoE4. Román 2005

14 Treatment of VaD Symptomatics Prevention Donepezil Galantamine
PROGRESS ACEI+DU 34% SYST:EUR -19/1000 Remedies are scarce. Vasodilators have been tried, as have pentophyllines and other drugs. The AChE-I Donezepil has been show to have effect on ADAS-cog after 24 weeks of tx. Galantamine has shown similar results, whereas Rivastigmine has not. Prevention is still the sharpest weapon. Besides prevention of recurrent strokes (30%), aspirin has not shown any additional benefits. The PROGRESS trial managed to show a 34% dementia risk reduction in 4Y with perindopril and indapamide and the SYST-EUR trial prevented 19/1000 patients from dementia in 5Y. Probably due to diminished number of strokes. Schemes for cognitive rehabilitation of stroke patients have been tried, but without consistent positive findings. Evaluation of early mobilisation on the effect of post-stroke cognitive impairment is underway as a substudy to the AVERT trial. Probably due to less strokes

15 Associations between dementias
89 of 419 pts studied DSM criteria for AD and dementia Known stroke for Dx of VaD Interrater reliability ROC-a 70-80% A lot of effort has been put into describing the scope of dementing disorders, in trying to establish what fraction of demented patients are due to what ethiology and to establish clinical and biological markers to better identify them. Maybe we try to dichotomise too much? The clinical pattern is different for the two largest dementing disorders, although probably not as clearcut as thought some years ago. The risk factors are pretty much the same, especially the modifiable ones. There is also a large entity of mixed dementias, not only due to diagnostic difficulties. Alzheimer’s disease is the most prevalent cause of dementia, although some claim that VaD is heavily underestimated. An american authopsy study of 89 patients found this contribution. However, one should note that arguments have been raised against neuropathology as a golden standard. The major objections are the great amount of “mixed” pathologies with doubtful clinical relevance and the fact that even though neuropathological critera can be strict, interrater reliability is often not too good.

16 Alzheimer’s Disease Steadily progressive Neurodegenerative disorder
Memory loss (anterograde) Spatial disabilities Plaques and tangles Familial AD subtypes – mutations identified Beta-amyloid and Tau protein ”hot” reserach topics Immunisation trials – mixed results Alzheimer’s disease is the most prevalent cause of dementia, although some claim that VaD is heavily underestimated. An american authopsy study of 89 patients found this contribution. In 2006 the worldwide prevalence of Alzheimer’s disease was estimated by the WHO to 27 million. By 2050, prevalence will quadruple by which time 1 in 85 persons worldwide will be living with the disease. About 40% of prevalent cases need a high level of care equivalent to that of a nursing home. Alzheimer’s disease is a steadily progressive neurodegenerative disorder. Hallmarks: Progressive loss of memory and spatial abilities with other higher cortical functions. Histology: beta-amyloid containing plaques and neurofibrillary tangles A asubgoup of familiar AD is accociated to mutations in genes coding for APP or presenilin genes, leading to increased levels of fibrillogenic A-beta. APP decreases the antioxidant capacity of the brain and activates microglia to produce neurotoxins. Also neuroprotective effects.

17 Association VaD – Alz 60-90% of AD patients show CVD at authopsy
Share risk factors Hypertension Skoog et al 1994 Atherosclerosis, ApoE Hofman et al 1997 Atrial fibrillation Ott et al 1997 AD increases stroke incidence Kalaria 1/3 of AD have cerebral infarcts Precumar et al2000 The two major dementing disorders are increasingly associated to each other. 60-90% of AD patients are found to have cerebrovascular disease at authopsy, which is more than the background risk. Hypertension is the major risk factor for stroke, but has been shown associated with cognitive impairment 15 years later. Arterial intima thickness is an indicator of vascular disease that has been associated to Alzheimer’s disease. Apo-lipoprotein E is a protein involved in the turnover of cholesterol in the human brain and its E4 allele has been linked to both AD risk and the incidence of stroke. ApoE is also involved in the metabolism of amyloid in the brain. Also atrial fibrillation – a classical stroke risk factor – has been shown to be associated to AD. Over 30% of AD pts show cerebral infarcts, many have haemorrhages and white matter changes. In nun study, AD pts with cer inf had worse dementia. In fact, a stroke increases the risk for AD by 3.

18 Amyloid αµνλον = starch Structure, not chemistry β-sheet configuration
Linear fibres, 7-10 nm No branches 4-6 protofilaments Congo red Dynamic - reversible The term ”amyloid” is the greek word for ”starch”, which Virchow, who coinded the term, studied. Amyloid is not one single protein, but rather a common structural configuration seen in various proteins. Signifies a misfoldning of the underlying wild-type protein into a highly organised beta-sheet, which in turn diminishies solubility, promotes aggregation and gives rise to deposits. The structure of aggregates is twines or chains of rigid, unbranched fibres, 7-10nm in length, commonly by 4-6. The formation is reversible, at least potentially. The factors promoting amyloid formation and un-formation is a key to understanding the pathoysiology of these disorders. Amyloidos has been coupled to many pathologies such as cardiomyopathises, renal and inflammatory disease, Alzheimer’s disease, (beta-amyloid), Parkinson’s disease (alfa-synuclein) and Huntington’s disease (polyglutamate inclusions)

19 Amyloid cascade hypothesis
The now classical hypothesis of the amyloid-forming chain reaction giving rise to neurodegeneration in AD was formed by Hardy and Higgins in 1992. A mis-cleavage of APP into Aβ, the fibrillar insoluble product which is neurotoxic, gives rise to neuronal death and AD. AD is characterized by the progressive deposition of the 4 kDa b-amyloid peptide (Aβ) in extracellular senile plaques. Aβ is a amino acid peptide derived by proteolytic cleavage of the amyloid precursor protein (APP), a Type I integral membrane protein. Cleavage of APP at the N-terminus of the Aβ peptide by β-secretase and at the C-terminus by γ-secretases constitutes the amyloidogenic pathway for processing of APP. The β-secretase was recently identified as an aspartyl protease (BACE or Asp-2), while γ-secretase activity is associated with the polytopic membrane proteins presenilin-1 and presenilin-2 In addition, APP can be processed by α-secretase which cleaves within the Aβ domain preventing deposition of this intact amyloidogenic peptide. a-secretase has many properties in common with the secretase that cleaves antiotensin converting enzyme, and is a zinc metalloproteinase of the (adamalysins) ADAMs family. The characterization of the APP secretases is important for the development of therapeutic strategies to control the build up of Aβ in the brain and the subsequent pathological effects of Alzheimer's disease. Upregulation of α-secretase activity by muscarinic agonists, cholesterol-lowering drugs, steroid hormones, non-steroidal anti-inflammatory drugs, and metal ions may explain some of the therapeutic actions of these agents in Alzheimer's disease. Hardy and Higgins ,1992.

20 Evidence FOR AGAINST Aβ + in familial AD Hardy, PNAS 1997
Aβ neurotoxic Loo, et al PNAS 1993 AGAINST Aβ deposits not associated to AD Neve, T Neurosci 1998 Not neuronal death in transgenic mice Chisti, J Biol Chem 2001 Support for the hypothesis include findings that the mutations in the familial variants of AD produce Aβ in higher quantities, and that Aβ has been demonstrated to have neurotoxic properties. However, findings are also aginst the hypothesis: Aβ is seen also in non cognitive impaired controls. Vast neuronal death is not always seen in transgenic mice overexpressing APP and learning and memory deficits don’t correlate to fibrillar Aβ. Soluble Aβ indeed seems to be better correlated to memory deficits than amylod plaques [McLean et al, 1999]

21 Amyloid and stroke APP mice get larger infarcts Larson, Brain Res 1999
External amyloid gives larger infarcts Whitehead et al, Stroke 2007 Often microhaemorrhages in AD Heyman, Neurology 1998 1/3 of AD have cerebral infarcts Precumar et al, Am J Pathol 1996 Aβ affects vascular reactivity Niwa et al, Am J Physiol 2002 Aβ induces inflammation Akiyama et al, ADAD, 2002 Does amyloid have a role also in vascular cognitive impairment? There sure are some indications: Transgenic APP-overexpressing mice do get larger infarcts after experimental stroke. Artificial high levels of amyloid show progressive increase in infarct size. Over 30% of AD pts show cerebral infarcts, many have haemorrhages and white matter changes. In nun study, AD pts with cer inf had worse dementia. In fact, a stroke increases the risk for AD by 3. Aβ has been shown to affect vascular tone, both in inducing vasoconstriction and in impairing autoregulation. Aβ is also associated to inflammatory activity after stroke, as the cerebral infarction in itself.

22 PIB-PET Visualises amyloid in vivo in the human brain 3x20 patients.
Acute stroke Cronic stroke Healthy controls Neuropsychiatric work-up Animal study in parallell So, does amyloid have a role also in vascular dementia? That seems to be a warranted question. In order to clarify the temporal and spatial distribution of amyloid after stroke and analyse its relation to cognitive impairment, we intend to use a novel PET marker known as ”the Pittsburgh compound” to do that in acute stroke patients, cronic stroke patients and healthy controls, 20 in each group and to follow them neuropsychiatrically for a year. We will recruit patients from the stroke ward at Austin, scan them acutely and 3 months later with blood samling and neuropsychiatry close to both scans. Due to John Ly, who studied PIB in tPA stroke patients, Early data show a pattern much different from what has previously reported, within large areas of the brain, mostly preilesionally but also at distant loccations, yield a heavy signal within hours from a stroke, then fading over a few weeks back to normal levels. In order to investigate the origin of the visualised amyloid, we well also perform animal studies in parallell. Our hopes are to shed further light on the intriguing presence of amyloid protein and its role in vascular cognitive impairment.

23 Post-stroke depression
”Discovered” 1977 Folstein 1977 Epidemiologically charted by many studies In acute stage (25-48%) Finklestein 1982; Schubert 1992; Wade 1987; Åstrom 1993; Rao 2001 First months(14-50%) Sinyor 1986; Morris 1990; Eastwood 1989; House 1991; Feibel 1982; Robinson 1982; Wade 1987; Åstrom 1993; Burvill 1995; Ebrahim 1987; Ng 1995; Pohjasvaara 1998; Kauhanen 1999; Appelros, 2004; Eriksson 2004 In the long run, >1år (12-42%) Morris 1990; Collin 1987; Wade 1987; House 1991; Åstrom 1993; Kauhanen 2000 , Linden 2007, White 2008 Systematic review of 51 observational studies: Approx 1/3 depressed Variations in methods make comparisons difficult Hackett 2005

24 Depression efter stroke - Frequency
Variation between studies Selection criteria Diagnostic instruments Time point after stroke Only a few use population- based controls Time from stroke, assessment instruments and diagnostic systems were far from uniform between the studies, making the results hard to interpret. There are also differences in study-base and selection of patients (23, 26). Patients in stroke studies are often younger and although it is generally recognized that depression is common after stroke, few studies have examined whether depression prevalence is increased in elderly stroke patients compared to age- and sex-matched controls. Only a few studies have used population-based control groups. One study (8) uses general practitioner records for selecting controls, but these were not sex-matched. A Danish study (27) that made diagnosis by cut-off values, used population-based controls, but did not publish risk estimates.

25 PSD - Causes Biological faktors
Ruptured aminergic projections; cortico-striatal, fronto-striatal, prefronto-subcortikal Strategic infarcts Right hemisphere, left anterior, left basala ganglia, inferio-frontal Catastrophic reaction to sudden serious loss of functions Pre-existing depressive personality unveiled The etiology of depression after stroke is debated as some authors put focus on biological factors i.e. disruption of tracts, such as aminergic cortico-strial (38, 39) fronto-striatal (40) or left-sided prefronto-subcortical pathways (41) or infarcts in strategic locations, such as right hemisphere strokes (42, 43), left anterior lesions (44), left-sided basal ganglia lesions (45) and inferior frontal lesions (46). Other studies emphasize the impact of sudden disability and loss of autonomy as a cause of reactive depression after stroke (47-50), and yet others try to join the two perspectives (51, 52).

26 Depression after stroke - consequences
Participation in / effect of rehablilitation lower Higher stroke-mortality Morris et al Am J Psych 1993; 150:124-9 More hospital care Schubert et al. Gen Hosp Psych 1992;14(1):69-76 More handicap Parikh et al. Arch neurol 1990;47:785-9 Less often discharged to independent living Cushman. Med Rehabil 1988;69:877-90 Social function worse Gordon et al. Arch Phys Med Rehabil 1985;66:353-94 Sexual function worse Monga et al. Arch Phys Med Rehabil 1986;67:19-22 The recognition and diagnosis of depression in stroke patients is important, as it has been associated with worse outcome in numerous studies (7, 12, 28-34) Nevertheless, depression after stroke is often underdiagnosed (35) despite that effective treatment exists (33, 36). Depressed stroke patients have more cognitive impairments (14), more days in hospital (35), utilize more care and are more often institutionalized than the nondepressed (37), but no quantitative estimation of the magnitude of how this impacts the health care delivery systems has so far been made (23).

27 Sensitive for intervention?
Systematic Review on Pharmacologic Treatment Hackett et al. Stroke 2005. No evidence for effect FINNSTROKE Study Kotila et al. Stroke. 1998 Active program after discharge Open patient rehab Activities in patient association Less w depression at 3 and 12 mån

28 However, there seems to be no support for the notion that PSD is a psychopathological entity different from depression in people without a stroke. We examined the symptom profile in depressed patients with and without stroke. The only items that differed significantly between stroke aptients and controls were ”sleep disturbances” and ”anhedonia” (or loss of interest). But the scores were higher for controls than stroke patients, indicationg that depression is not overestimated in stroke patients due to somatic symptoms and also that there is no reason to believe that what is proven effective for depression is that also in PSD. Absence of evidence is not evidence of absence!

29 CognitivE NeurorehabilitATION

30 Intervention paradigms
C. Adapt B. Compensate A. Repair Thomas Lindén 2006

31 Neurobiological basics
Different time frames Control spread of injury Restore blood flow, diminish edema, normalise chemical environment (pH, ions, lactate, radicals) Not only regain, but reorganise brain functions Neurogenesis can be stimulated and directed With pharma, but also with environmental factors Hillis 2005 Thomas Lindén 2006

32 Neurobiological basics
Top-down-stimulation Attention training can ameliorate prerequisites for healing in primary and secondary cortex Desimone 1995 Bottom-up-stimulation EMG-amplification Hummelsheim 1995 Supported walk taining Hesse 1995 Inhibitory processes Competition between hemispheres Kinsbourne 1993 Constraint-induced therapy Noradrenergic/cholinergic transmission facilitates plasticity Will 1992 Positive experiments w d-amphetamine in language training Negative influence of NA/Ach-modulating pharma Thomas Lindén 2006

33 Plasticity Hebbian learning
Cognition is communicating cell networks and connections that are used are strenghened ”Cells that fire together, wire together” The brain reorganises (and repairs) itself by constant synapse turnover Rehabilitation after damage has same mechanisms as normal learning and experience dependant plasticity Varying input to damage neuronal circuits will increase synapses and affect rehabilitation Rent logiskt – om två kretsar vars koppling brutits genom en skada båda samtidigt stimuleras, kommer de att successivt återhämta sig

34 Val av patienter för rehabilitering
Patienter som inte skall inkluderas i rehabiliteringsprogram: Patienter som kommer att återhämta sig utan rehabilitering Patienter som inte återhämtas trots rehabilitering Vilka skall således väljas ut till rehabilitering? De patienter som utan rehabilitering inte förbättras men som gör det med rehabilitering Identifierar vi vilka dessa patienter är och väljer vi idag rätt patienter till rehabilitering? Thomas Lindén 2006

35 Which patients benefit from rehabilitation?
Stationär eller endast långsamt progredierande sjukdom I förhållande till beräknade effekter av rehabiliteringen Viss kvarvarande funktion T.ex. dålig förutsättning för minnesträning hos patient med amnesi Isolerad funktionsförlust T.ex. uppmärksamhetsstörning, men intakt minne Deprimerade patienter Uppmärksamma och åtgärda först Missbruk, svåra sociala förhållanden Thomas Lindén 2006

36 Intervention Multiple simultaneous strategies
Bostads-/arbetsplatsanpassning Kompensatoriska strategier Hjälpmedel Speciella rehabiliteringstekniker Direkt instruktion Felfri instruktion Procedurlärande Hantera känslomässiga reaktioner Undervisning Beteendepsykologisk intervention OBS! Olika strategier kan motverka varandra Man stimulerar reparation OCH hittar andra sätt att lösa uppgiften OCH ändra miljön och dess krav Använda friska handen motverkar läkning av den skadade Personlig assistent gör att patienter sämre lär sig klara sig själv För uppmärksamhetsstörning är det enligt Cicerone 2000 bäst att kombinera läkande behandling med uppmärksamhetsträning. Mateer 2005 Thomas Lindén 2006

37 Miljöanpassning Säkerhet – undvika olyckor och självskador
Ex: spis, trappor, varmvatten, eld, bil Minimera överstimulering Bakgrundsljud, starkt ljus, rörelser Anpassa till uttröttbarhet Schema för vila, rutiner Motverka specifikt funktionshinder Etiketter på lådor, anslagstavla, prylsanering Checklistor, exvis för morgonrutin Klocka, kalender Ducharme 1999, Martelli 1999, Thompson 1999, Sohlberg 2001 Thomas Lindén 2006

38 Hjälpmedel och kompensatoriska strategier
Stor variation för kognitiva skador Minnesstöd Kalender, klocka med datum, kom-ihåg-bok, dator Hjälp med initiering Alarm, PDA, mobiltelefon Uppmärksamhetsstörningar ”Harar” (Visual cue devices) Individuell anpassning är nyckeln! Kim 1999, Wilson 2001, Wright 2001 Thomas Lindén 2006

39 Regain function Träna nedsatt förmåga för att öka den
Uppmärksamhetsstörning Van Zomeren 1984, Posener 1990 Länkade kognitiva förmågor Uppmärksamhetsträning förbättrar möjlighet att lära nytt, delta i samtal eller lösa problem Ge uppgifter som kräver flera förmågor Strategiträning och feedback viktigt Mät Individualisera! Park 1999, Cicerone 2000, 2002 Thomas Lindén 2006

40 Special training techniques
Skall fungera trots brister i minne, uppmärksamhet, koncentration, uttröttbarhet Några exempel Direktinstruerande inlärning Felfri (errorless) inlärning Procedurinlärning Thomas Lindén 2006

41 Direct instruction learning
Designat för fortsatt, kontinuerligt lärande enligt i förväg uppgjord plan Nedbrytning av uppgift i mindre delar och inlärning av komponenterna Noggrant val av skolexempel, så lärandet bygger på tidigare erfarenheter Individualiserad takt och svårighetsgrad Framgångsrikt vid hjärnskada Glang 1992 Thomas Lindén 2006

42 Error-free learning Inlärning börjar på en nivå patienten behärskar
Eftersom patienten aldrig tar miste, undviks att felaktigheter präglas in Minskar stress och frustration i inlärningen Förbättrar inte minnet, men utnyttjar bättre den minneskapacitet patienten har Använt vid instruktion av minnesskadade t.ex vid faktainlärning och (enkel) beteendeinlärning Wilson 1994 Thomas Lindén 2006

43 Procedurinlärning Bygger på idén att bättre procedurminne ger stöd till ett skadat semantiskt minne. Squire 1992 Förmågan till procedurinlärning är ofta relativt välbevarad vid t.ex. TBI och stroke. Ej fullgott utvärderad nytta Fem (långtids-)minnesmodaliteter: Procedurminne Koppla samman flera stimuli eller aktiviteter till kedjor, t.ex. cykling Priming-minne Känna igen helheter från mindre och mindre detaljer Perceptuellt minne Igenkänning av objekt, t.ex. baserat på grupperingar och likheter Semantiskt minne kontextfritt. Huvudstaden i Albanien. Kan uppgiften, men inte hur man lärt sig den. Episodiskt minne Autobiografiskt minne; affektkopplat, kontexter. Minnas tillbaka! Thomas Lindén 2006

44 Some particular conditions

45 Attention disorders

46 Uppmärksamhetsstörning
Mycket vanlig Viktig i nästan alla aktiviteter Ingen visad effekt av direkt träning I motsats till t.ex. motoriska skador Träning i kompensationsstrategier ger bra resultat (dvs uppgiftsorienterat) Förstå hur patientens brist ser ut och träna aktiviteter utifrån dessa med klara målsättningar Träning i självinstruktion bör ingå. Webster 1983 Thomas Lindén 2006

47 Uppmärksamhetsträning
Stöd för att naturalistic action-träning ger resultat Flera typer av instruktion bra för lätt men inte svårt skadade Park 2005 Berätta samtidigt som uppgiften demonstreras et c. Kortare, återkommande bättre än hopad Individualiserad målsättning, behandling och uppföljning ger bättre resultat. 1tim bättre än 2, åtminstone veckovis träning Task-oriented: kaffekokning, bilkörning, arbetsuppgifter, pluggande Sohlberg 2003 Thomas Lindén 2006

48 Time Pressure Management
Träning i att välja strategi för problemlösning Tänka efter innan om alla uppgifter hinns med under den tid som står till buds Planera utförandet innan uppgiften startar Handlingsplan för tidsnöd Följa den uppgjorda planen (självinstruktion) Kompenserar för dålig simultankapacitet och stressintolerans Effekt på inlärning kvar efter 6 mån Fasotti 2000 Thomas Lindén 2006

49 Memory impairment

50 Where is memory located?
Hippocampus central för inprägling Skada ger anterograd amnesi Frontalcortex central för retention Skada ger retrograd amnesi OBS! Grovt förenklat. Många strukturer samverkar i minnesfunktionen. Thomas Lindén 2006

51 Memory impairment– possible to rehabilitate?
Ingen metod har visat effekt på att återfå förlorad minnesfunktion Glisky 2005 Minnesskadade kan lära sig strategier för att bättre utnyttja ett dåligt minne Heinrichs 1992 Fokus blir disability och inte impairment Endast lätt till måttligt skadade Thomas Lindén 2006

52 ExeCutive impairments

53 Executive impairments
Samlingsbegrepp för del av frontallobssyndromet Vanligt vid traumatisk hjärnskada Komplicerade teorier om mekanism, inget koncensus Påverkar rehabilitering av andra funktioner Thomas Lindén 2006

54 Executive impairments
Vanliga symptom Impulsivitet Disinhibition Perseveration Avledbarhet Planeringsoförmåga (sekventiellt tänkande) Dåligt abstraktionsförmåga Hänsynslöshet Apati Stuss&Benson 1986 Thomas Lindén 2006

55 Executive impairments
Diagnos/Bedömning Wisconsin Card Sorting Test Verbal Fluency Abstrakt tänkande Sekventiella uppgifter Samtidiga uppgifter (multi-tasking) Thomas Lindén 2006

56 Executive impairments
Ingångar till Rehabilitering Substitution snarare än reparation Läkemedel Dopamin- (Bromokriptin, Amantadin) och noradrenalin-agonister (Idazoxan) Uppgiftsorienterad träning fungerar Evans 2005 Goal Management Training Bryta ned och målsätta uppgifter Levine 2000 Time Pressure Management Fasotti 2000 Hjälpmedel för igångsättning och påminnelser Läkemedel endast effekt i små studier. Däremot exekutiv störning som biverkan vid Sch-behandling GMT effekt på enstaka aktiviteter i små material Princip: Personer med frontallobsskada saknar förmåga att bryta ned en uppgift till listor av aktiviteter att utföra och/eller stämma av aktiviteter mot den övergripande planen för arbetet. GMT lär ut att bryta ned uppgiften i mindre delar enligt ssk mönster. TPM visat resultat på specifika uppgifter, men inte i vardagslivet Thomas Lindén 2006

57 Cognitive rehabilitation after traumatic brain injury

58 Studies on patients with traumatic brain injury
Kompensatoriska hjälpmedel Som anteckningsblock, larm, PDA, har visat effekt på vardaglig minnesfunktion Wilson 2001, Schmitter-Edgecombe 1995 Effekt på ångest, relationer och självuppfattning, dock inte bestående Helfenstein 1982 Datorstödd träning gav effekt på minnestest, men inte i vardagen Grealy 1999, Kerner 1985, Thomas-Stonell 1994, Twum 1994, Gray 1992 TPM Effekt på datauppgift, ej på minne Fasotti 2000 Uppmärksamhetsträning Färre självrapporterade minnesfel McMillan 2002 Miljöorienterad rehabilitering Endast effekt på arbetsåtergång för de som varit medvetslösa >1h, inte i hela gruppen Salazar 2000 Komp hjm en liten RCT+en obs stud (Wilson 1997) Thomas Lindén 2006

59 Studies on patients with traumatic brain injury
GMT Viss effekt på beteende Levine 2000 Uppgiftsorienterad kognitiv träning Effekt på arbetsåtergång efter ett år Parente 1999 Thomas Lindén 2006